Currently, the use of microscopical examinations alone is insufficient for the histological classification and grading of gliomas. In recognition of the emerging role of molecular diagnostic approaches to glioma classification, the role of genetic profiles has been emphasized on, as in the distinct subtypes of glioma. Glioblastomas (WHO grade IV) may develop de novo (primary glioblastomas) or through progression from lower-grade astrocytomas (secondary glioblastomas) both glioblastomas show similar histological features. However, these subtypes of glioblastoma involve distinct disease entities that evolve through different genetic pathways and are likely to differ in prognosis and response to therapy. Oligodendroglioma is recognized as a particular subtype of gliomas that shows remarkable response to chemotherapy [procarbazine+CCNU+vincristine (PCV)], making their correct diagnosis important. However, the histological differentiation of oligodendrogliomas from diffuse astrocytoma could be highly subjective in cases without typical morphological features. Loss of heterozygosity (LOH) on chromosomes 1p and 19q is correlated with sensitivity to PCV chemotherapy with increased survival in anaplastic oligodendroglioma cases (WHO grade III). Similarly, combined LOH on 1p and 19q has been identified as a predictor of favorable overall survival in oligodendrogliomas. Additionally, the status of the O6-methylguanine-methyltransferase gene (O6-MGMT) is associated with resistance to temozolomide (TMZ). We have previously found methylation or expression mosaicism of O6-MGMT in gliomas, resulting in problems on tumor sampling and response to TMZ. An assessment of the O6-MGMT methylation mosaicism in heterogeneous glioma may provide a more accurate assessment for the response to TMZ. This article suggests that more biological and molecular approaches to brain tumor classification will provide improved means to treat these tumors.